Beta-amyloidprecursor protein

Hydropathy plot Membrane Bound

Sequence Alignment

Sequence Alignment

19F and 20F

Beta-secretase cut site

AA 41 and 42

Extracellular Domain

(1owt)(1mwp)

(1rw6)

Beta Sheets = greenAlpha Helices = purpleLinks between regions color coded

Extracellular Domain

• Not much is known about the extracellular domain function.

• Somewhat involved with neural growth and plasticity.

• Found in many different cells throughout the body

Membrane Domain (1iyt)

Green = amino acids 41 and 42

• Membrane Domain is composed of two helices and turn in between

• Quaternary structure has overlapping alpha helices

Membrane (Tertiary structure)

Beta-secretase (2fkn)

• Aspartyl protease that clips APP at the start of the membrane domain

• Yellow = beta sheets• Pink = alpha helices• Asp 32 and 215 are the

active site proteases.

Side-chain interaction of Amyloid-Beta domain (1iyt)

Phe 20

Phe 19

• Adjacent phenylalanine residues provide hydrophobic π-stacking interactions

• There is also a salt bridge formed by K16 and D22

Alzheimer’s disease(2beg)

• Linked to buildup of amyloid-beta plaques

• Form complex beta-sheet fibrils

Alzheimer’s disease

• Tertiary structure of the Amyloid beta plaque– All Beta Sheets and

linkers– Insoluble in cytosol and

polar solvents.

References• 1.) C. Morgan, M. Colombres, M. T. Nunez & N. C. Inestrosa (2004)

Structure and function of amyloid in Alzheimer's disease. Progress in Neurobiology 74, 323-349.

• 2.) Berhanu, W. M., and Hansmann, U. H. E. (2012) Side-chain hydrophobicity and the stability of Aβ16–22 aggregates. Protein Sci. v21(12), 1837-1848.

• 3.) Crescenzi, O., Tomaselli, S., Guerrini, R., Salvadori, S., D'Ursi, A. M., Temussi, P. A. and Picone, D. (2002), Solution structure of the Alzheimer amyloid β-peptide (1–42) in an apolar microenvironment. European Journal of Biochemistry, 269: 5642–5648. doi: 10.1046/j.1432-1033.2002.03271.x

• 4.) Petkova, A. T., Yau, W., and Tycko, R., (2006) Experimental constraints on quaternary structure in Alzheimer's β-amyloid fibrils. NIHPA Biochemistry. 45(2), 498-512.